Diabetes is a widespread disease present throughout the world and is associated with major clinical complications including microvascular complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, and macrovascular complications such as atherosclerosis, peripheral vasculopathies, myocardial infarction and stroke.
The insulin resistance that characterises diabetes is also involved in syndrome X, in polycystic ovary syndrome, in obesity, in hypertension, in hyperlipidaemia and in hypercholesterolaemia (J. Am Osteopath Assoc 2000 October; 100(10):621-34; JAMA 2002 November 27; 288(20):2579-88).
Hyperlipidaemia, hypercholesterolaemia and hypertension are known to play a decisive role in the onset of coronary heart disease (CHD).
An increase in protein glycosylation is also known to be involved in the above-mentioned complications of diabetes (Diabetologia 2001 February; 44(2):129-46).
Said complications constitute a serious threat to the health and well-being of the individual.
Different clinical forms of diabetic disease are known, the most common being type 2 and type 1 diabetes. Type 2 diabetes is characterised by a reduced sensitivity to the action of insulin (insulin resistance) and gives rise to an increase in insulin levels in the body in an attempt to compensate for this defect and to a consequent increase in glucose levels. There have been numerous reports confirming that insulin resistance is involved in many disease conditions other than type 2 diabetes itself, such as dyslipidaemia, obesity, arterial hypertension, fatty liver and certain macrovascular and microvascular characteristics of diabetic disease itself. The association between insulin resistance and obesity, hypertension and dyslipidaemia is known as syndrome X.
For the treatment of type 2 diabetes, a number of drugs have been on the market for some time now such as the biguanides and sulphonylureas. The best known of the biguanides is metformin but its mechanism of action is not clear and it presents side effects such as gastrointestinal disorders and the danger of acidosis in conditions of renal, cardiac, hepatic, pulmonary insufficiency, etc. The sulphonylureas promote the secretion of insulin by the β-cells and have episodes of hypoglycaemia as a possible side effect. In addition, all the monotherapies with sulphonylureas or with metformin are doomed to failure in the long term (UKPDS Study).
Recently introduced onto the market are the thiazolidinediones, which are insulin-sensitising antidiabetic agents such as troglitazone (J. Med. Chem., 1989, 32, 421-428), pioglitazone (Arzneim. Forsch./Drug Res., 1990, 40 (1), 37-42), and rosiglitazone (Bioorg. Med. Chem. Lett., 1994, 4, 1181-1184) which are capable of reducing diabetic hyperglycaemia and insulin levels. The side effects already established for troglitazone and feared for other compounds belonging to this class are: liver toxicity (which has led to the withdrawal of troglitazone from the market in the USA), increased LDL-cholesterol, weight gain and oedema.
These compounds are synthetic ligands with high affinity for Peroxisome Proliferator Activated Receptor γ (PPARγ) (J. Biol. Chem., 1995, 270, 12953-12956).
Peroxisome Proliferator Activated Receptors (PPARs) are receptors belonging to the superfamily of the nuclear receptors whose function is to control the expression of genes involved in carbohydrate and lipid metabolism (J. Med. Chem., 2000, 43, 527-550). Various subtypes of PPARs have been identified: PPARγ, PPARα and PPARβ (also known as 6). The gamma isoform (PPARγ) is involved in the regulation of the differentiation of adipocytes and in energy homeostasis, while the alpha isoform (PPARα) controls the oxidation of fatty acids resulting in modulation of the lipid levels in plasma. It is important to note that the reduction of lipids, which is obtained in rodents with PPARγ agonists such as rosiglitazone, is hardly to be found in human subjects, whereas the lipid reduction caused in rodents by fibrates is confirmed in humans. A correspondence between activation of the PPARγ receptor and serum-glucose-lowering activity has been confirmed in structure-activity relationship studies aimed at identifying new molecules with potential antidiabetic action (J. Med. Chem., 1996, 39, 665-668; J. Med. Chem., 1998, 41, 5020-5036; 5037-5054; 5055-5069). The insulin-sensitising action would appear to be related to the fatty acid recruitment action regulated by the activated PPARγ receptor, which is thought to lead to an improvement in the insulin resistance of the tissues by improving glycaemia and lowering insulin levels (Diabetes, 1998, 47, 507-514).
Over the past few years mixed-profile molecules have emerged, i.e. ligands of PPARγ and PPARα (KRP 297, Diabetes, 1998, 47, 1841-1847; DRF 2725, Diabetes, 2001, 50, suppl. 2, A108; AZ 242, Diabetes, 2001, 50, suppl. 2, A121-A122; WO 01/16120). It is in this context that we should view the very recent publication of a Smithkline Beecham patent (WO 02/067912 published on 6 September 2002) which refers to a new class of compounds defined as “PPAR pan-agonists”, i.e. agonists capable of activating all three PPAR isoforms so as to minimise the unwanted side effects of PPARγ activation. In particular, this new class of antidiabetic agents, though maintaining the characteristics typical of PPARγ activation, are thought to lead to less weight gain and milder oedema. These compounds are potentially capable of exerting good control of diabetic disease by presenting a serum-glucose-lowering and serum-lipid-lowering action with fewer of the side effects typical of the first series of compounds in the thiazolidonedione class, which were exclusively ligands of the PPARγ receptor. The structures claimed in patents WO 01/16120 and WO 02/067912 share the characteristic in common that they present a fibrate-like portion.
Not all the scientific community, however, agrees with what has been outlined here above. In fact, studies regarding new-generation compounds, whether thiazolidinedione derivatives or not, (MC555, J. Biol. Chem., 1998, Vol. 273 (49), 32679-32684; NC2100 Diabetes, 2000, 49, 759-767, YM440, Metabolism, 2000, 49, 411-417), in gene transactivation tests, in-vitro experiments on glucose uptake with muscle tissue, and in-vivo experiments in transgenic animals with deficient expression of the PPARγ receptor, have suggested there may be no direct relationship between activation of the PPARγ receptor and the serum-glucose-lowering and serum-lipid-lowering activity of these compounds (Toxicology Letters, 2001, 120, 9-19).
By way of confirmation of this, there are a number of investigators who have chosen to use in-vivo screening of diabetic animals (db/db mice, ob/ob mice) in order to identify possible insulin-sensitising agents which are not necessarily good PPAR ligands. From these experiments a number of compounds with interesting antidiabetic activity have been selected and are still in the course of study in animal models (DRF 2189, J. Med. Chem., 1998, 41, 1619-1630; JTT-501, J. Med. Chem., 1998, 41, 1927-1933).
The scientific community would now seem to be oriented towards a search for new compounds with a different mechanism of action which have a similar or superior effect on insulin sensitivity and glucose homeostasis without toxic effects (J. Med. Chem., 2001, 44, 2601-2611) and which are endowed with serum-lipid-lowering activity superior to that of both the old and new antidiabetic agents currently in use.
Hyperlipidaemia is a severe aspect of diabetic disease, constituting, together with the hypertension that is often present, a risk factor for atherosclerosis and for cardiovascular disease which is the first cause of death in diabetes.
The need to reduce the lipids in the blood is often tackled using fibrates, which, despite the positive results obtained in insulin resistance, have never proved successful as serum-glucose-lowering agents.